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Therapeutic Revolution in Rheumatoid Arthritis Brian J. Keroack, MD Rheumatology Associates Portland, Maine
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Rheumatoid Arthritis Morning stiffness>1 hour Usually symmetric Parameters of systemic inflammation >6 weeks duration 70% +RF
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Rheumatoid Arthritis Accepted Prevalence: 1- 1.5% (classic seropositive) 200,000 new cases annually 19.9 billion/year spent on RA. 9.5 billion dollars/million patients. This exceeds cost/patient in diabetes and cardiovascular disease. Rheumatoid Arthritis affects Survival:
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Impact of RA Premature mortality Increased morbidity Significant impact on quality of life – Pain with associated functional disability – Fatigue 73% of patients 42% with severe fatigue – Depression Economic impact – Work dysfunction – Earnings loss of approximately 50%
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Clinically Detectable Damage Occurs Early in RA MRI-detectable erosions are present within 4 months of symptom onset 1 Most patients (up to 93%) with RA of < 2 years’ duration show radiographic damage 2 Disease progression is more rapid during the first year than during the second and third years 3
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Cartilage in RA: Target or Bystander? Early: – Cytokines (IL-1, TNF- ): Macrophages – Catabolic Effects on Chondrocytes – Proteoglycan Depletion – Weakens ability to rebound from a load Next: – Induction of Metalloproteinases—Stromolysin, Collagenase Last: – Phagocytosis of Cartilage by Pannus
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TNF- is a pivotal cytokine in the pathogenesis of RA Mediates pathologic inflammation Mediates joint destruction Mediates systemic, extra-articular symptoms of inflammation Regulates levels of adhesion molecules responsible for leukocyte migration
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Parameters of Inflammation
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Approach to the Treatment of RA Try to figure out ‘what type’ of Rheumatoid Arthritis the patient has This is not a uniform disease – Young, Sero-positive patient vs. Older Sero- negative patient. – Abrupt vs gradual onset – Response to 10-15 mg prednisone (‘Lourdes’ response) Mild DMARDS vs Immunosuprssives
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Approach to the Treatment of RA: Early Immunosupression Antiproliferative agents – More aggressive doses of methotrexate – Leflunomide Biologics – Infliximab/ Etanercept/Humira (TNF- ) – Kineret (IL-1ra) – Orencia (abatacept) Rituxan (B-cell depletion) – MRA (IL-6 receptor) – Small Modular Immunopharmaceutical (SIMP) Combination therapy—sooner than ever before
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Weinblatt Study
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Methotrexate Multiple Trials Support Use DMARD of Choice (but there are challengers) Long Term Efficacy/Compliance Radiographic Data Relatively Rapid Onset of Action (4-8 weeks) Dosage 7.5-25mg/week (above 20 mg inject) I still try Methotrexate in Most RA patients before moving on to Newer DMARDS—but I move faster to Biologics in partial responders (2-3 months) —patience is NOT a virtue here. I would never give you a drug worse than your disease
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Etanercept Activatedmacrophage Targetcell Signal sTNFR TNF TNFR Etanercept TNF Inhibition: Etanercept
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Methotrexate Etanercept 25 mg Patients with baseline erosions 86%(25/29) 96%(24/25) 52%(98/188)72%(130/181) 57%(123/217) 75%(154/206) All patients P < 0.001 Patients With No New Erosions at 1 Year P < 0.001 P = 0.159 Patients with no baseline erosions Finck B. Arthritis Rheum. 1999.
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Antibody Neutralization of TNF
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Infliximab in Active RA Despite MTX ATTRACT Improvement in Swollen Joints MTX Control 3 mg/kg q 8 wks 10 mg/kg q 8 wks MTX Control 3 mg/kg q 4 wks 10 mg/kg q 4 wks
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Infliximab in Active RA Despite MTX ATTRACT Improvement in Tender Joints MTX Control 3 mg/kg q 8 wks 10 mg/kg q 8 wks MTX Control 3 mg/kg q 4 wks 10 mg/kg q 4 wks
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Infliximab in Active RA Despite MTX ATTRACT Median C-reactive Protein (mg/dL)
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*P<0.05 for HUMIRA + MTX vs MTX alone and HUMIRA alone † Normal CRP was defined as ≤ 0.5 mg/dL * * * * Percentage of Patients * TJC=0SJC=0HAQ=0Morning Stiffness=0 Normal CRP † PREMIER 2-Year Results of Selected Clinical Responses Emery P, et al. Presented at: EULAR; June 8-11, 2005; Vienna, Austria. Data on file, Abbott Laboratories. (n=268) (n=257) (n=274)
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So What is the Catch? Cost = $17,000-25,000/year Injections or infusions Profound immunosupression – Careful who you put on the drug (Diabetes, COPD, Renal failure, etc) – When patients present with infection, they have more subtle complaints—fewer ‘systemic’ symptoms occur – Low threshold for antibiotics as most serious infections are ‘typical’ – Can you educate the patient?
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The Other Biologics Orencia: Approved by FDA 2/2006—Role unclear—does work in TNF failures Rituxan: 2 doses can produce a protracted period of remission in refractory RA— Infusion reactions (1-2%)
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Orencia—CTLA4-Ig
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Rituxan
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Bridge to the 21 st Century Early aggressive therapy especially in young seropositive patients—DMARDS within 3 months of diagnosis. Best chance for remission Methotrexate first—But in partial responders rapidly move to TNF- blockers. The data suggest the they should be ADDED to Methotrexate. Biologics to induce early remissions for those with erosions at diagnosis. Try more than one TNF- blocker (70% respond to a switch) Orencia/Rituxan in TNF- Failures ?Low dose prednisone (5-10 mg) combined with osteoporosis protection—Many need it for symptoms NSAIDS/COX-2 as bridge therapy in mild Rheumatoid Arthritis (essentially worthless)
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Future? MRA ?—IL-6 receptor antibody (+/- data to date and multiple problems—LFT’s, GI bleeding?) probably not a ‘player’ SIMP’s: these are single chain polypeptides with greater tissue penetration—high affinity --??greater efficacy We are in the ‘infancy’ of immune ‘manipulation’
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